title: Age-associated impairment of Akt phosphorylation in primary rat hepatocytes is remediated by alpha-lipoic acid through PI3 kinase, PTEN, and PP2A.
abstract: Akt is a highly regulated serine/threonine kinase involved in stress response and cell survival. Stress response pathways must cope with increasing chronic stress susceptibility with age. We found an age-related lesion in Akt activity via loss of phosphorylation on Ser473. In hepatocytes from old rats, basal phospho-Ser473 Akt is 30% lower when compared to young, but basal phospho-Thr308 Akt is unchanged. (R)-alpha-lipoic acid (LA), a dithiol compound with antioxidant properties, is effective against age-related increases in oxidative stress and has been used to improve glucose utilization through insulin receptor (IR) pathway-mediated Akt phosphorylation. Treatment with physiologically relevant doses of LA (50 microM) provided a 30% increase in phospho-Ser473. Furthermore, two phosphatases that antagonize Akt, PTEN and PP2A, were both partially inhibited by LA. Thus, LA may be a nutritive agent that can remediate loss of function in the Akt pathway and aid in the survival of liver cells.
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512, USA. kate.shay@oregonstate.edu
authors.forename: Kate Petersen
authors.initials: KP
authors.lastname: Shay
authors.forename: Tory M
authors.initials: TM
authors.lastname: Hagen
mesh_terms: D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002470:Cell Survival; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D007328:Insulin / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D012694:Serine; D015398:Signal Transduction / Q000187:drug effects; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D007328:Insulin; D012694:Serine; D008063:Thioctic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat